Core Data Set CYP2D6 Metabolism Oxidised metabolites seen in pre-clinical species Inhibitor Target CYP Isoform CLint (µl/min/mg protein) % Inhibition Control 12.5 - Furafylline 1A2 12.9 0 Sulfaphenoxazole 2C9 11.9 4 Omeprazole 2C19 11.7 6 Quinidine 2D6 6.9 45 Ketoconazole 3A4/5 10.6 15 Trimethoprim 2C8 11.5 8 1
Opinion of the group: 2D6 metabolism associated with significant clinical experience, particularly with respect to poor metabolizers The consensus of the group was to identify 2D6 PMs Prospective genotyping proposed Possible design: Volunteers with increasing dose Exclude PMs initially Include PMs at low dose once higher dose tolerated by EMs Conclusion: everyone wants PM information e.g. exclude PMs from initial studies.
Variation 1 CYP3A4/5 Metabolism As per core set, but metabolism is via CYP3A4 Inhibitor Target CYP Isoform CLint (µl/min/mg protein) % Inhibition Control 12.5 - Furafylline 1A2 12.9 0 Sulfaphenoxazole 2C9 11.9 4 Omeprazole 2C19 11.7 6 Quinidine 2D6 10.6 15 Ketoconazole 3A4/5 6.9 45 Trimethoprim 2C8 11.5 8 3
Opinion of the group CYP3A4/5 with poorer correlation between genotype and phenotype As a result, the consensus of group: Do nothing, collect DNA If Blacks: somewhat more important for 3A5 genotyping
Variation 2 CYP2C8 Metabolism As per core set, but metabolism is via 2C8 Inhibitor Target CYP Isoform CLint (µl/min/mg protein) % Inhibition Control 12.5 - Furafylline 1A2 12.9 0 Sulfaphenoxazole 2C9 11.9 4 Omeprazole 2C19 11.7 6 Quinidine 2D6 10.6 15 Ketoconazole 3A4/5 10.5 15 Trimethoprim 2C8 5.6 55 5
Opinion of the group CYP2C8 with poor-metabolizer alleles However, limited clinical literature on the impact on drug metabolism Consensus of group: DNA collection only, no pro-active genotyping (c.f. CYP2D6) Weak penetrance of alleles Do CYP2C8 genotyping, when PK or other outliers are identified later during development
Variation 3 No Oxidised Metabolites As per core dataset, but no oxidative metabolites seen in pre-clinical species compound excreted unchanged in faeces Inhibitor Target CYP Isoform CLint (µl/min/mg protein) % Inhibition Control 12.5 - Furafylline 1A2 12.9 0 Sulfaphenoxazole 2C9 11.9 4 Omeprazole 2C19 11.7 6 Quinidine 2D6 6.9 45 Ketoconazole 3A4/5 10.6 15 Trimethoprim 2C8 11.5 8 7
Opinion of the group Absence of oxidised metabolites suggests that in vitro metabolism may not be relevant in vivo Consensus: DNA collection only, no pro-active genotyping (c.f. core case) Some attention warranted regarding effect in relation to the UM (and PM) phenotypes, in case UMs generate oxidised metabolites in humans
Variation 4 Reduced CYP2D6 Metabolism As per core set, except that CYP2D6 specific metabolism is 22% (as opposed to 40%). Inhibitor Target CYP Isoform CLint (µl/min/mg protein) % Inhibition Control 12.5 - Furafylline 1A2 12.9 0 Sulfaphenoxaz 2C9 11.9 4 ole Omeprazole 2C19 11.7 6 Quinidine 2D6 9.8 22 Ketoconazole 3A4/5 11.8 5 Trimethoprim 2C8 11.5 8 9
Opinion of the group Weak CYP2D6 metabolism, with uncertain relevance Divergence in opinions in group: Determine the non-metabolised clearance 2D6 genotyping for safety issues PMs identified later in development Enriched studies on defined phenotypes
Transporter Studies Increasingly, transporters implicated in drug disposition, efficacy and safety Compound A (target organ liver) tested for uptake in cells transfected with human OATP receptors, including known polymorphisms Data for OATP sub-types expressed as rate of uptake into transfected cells Data for OATP1B1 variants expressed as percentage activity of wild-type transporter 11
OATP Transport Data OATP Subtype Rate of Uptake (A.U) OATP1B1 Variant Frequency Vehicle 0.8 *1a 0.56 12.5 Rate of Uptake (A.U) 1A2 4.5 *1b 0.26 10.2 1B1 12.5 *5 0.02 1.5 1B3 6.2 *15 0.16 4.5 2B1 3.5 The data show significant uptake by OATP1B1, which is greatly reduced in known human variants Some uptake is seen with other OATP subtypes 12
Opinion of the group As yet, few examples linking genotype variants to clinical outcome Consensus to collect DNA in phase I studies A majority recommends prospective genotype studies in phase I Agreement that genotyping is necessary during phase IIa efficacy studies
General aspects Ethics committees need to understand the value of prospective DNA collection still an issue DMET chips patients numbers are too small in phase I DMET chips can be used the whole phase clinical trials Focus is often on PMs. However, UMs important for metabolite formation (for safety) and during Phase II (for efficacy). Clinical experience was the critical factor driving pro-active PGx in phase I